Abstract: Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

INTRODUCTION

Despite early diagnosis and the availability of more active treatments, breast cancer remains a major public health problem.1 To date, early-stage breast cancer is treated with curative intent by surgery with or without adjuvant treatments, including chemotherapy, endocrine therapy, targeted agents, and radiotherapy.2–4 However, ~20%–30% of women will relapse, despite optimal adjuvant therapies.5,6 Furthermore, these treatments and, particularly, chemotherapy are associated with significant toxicities that can alter the short- and long-term quality of life of cancer survivors.7 This underlies an unmet need to implement more effective therapies with acceptable toxicity profile for breast cancer patients with early-stage disease.

Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of treatments.8 In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells is related to a distinctive molecular signature as compared to HER2-negative tumors.9,10 Indeed, HER2-positive breast cancers are poorly differentiated and characterized by having high grade, high rates of cell proliferation and lymph node involvement with a relative resistance to chemotherapies, and a greater likelihood of developing distant metastases.8 Interestingly, the expression of the HER2 protein in tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab and its approval in 1998 for the treatment of patients with metastatic disease radically changed the natural history of this subtype of breast cancer.11,12 These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of anti-HER2 targeted agents not only in the metastatic setting but also in the early setting.13 Chemotherapy plus 1 year of trastuzumab is the current standard of care for patients with early-stage HER2-positive breast cancer.2–4 Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

HER2 PATHWAY IN BREAST CANCER

The HER (ErbB) receptor family includes HER1 (ErbB1 or EGFR), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4) that act mechanistically through tyrosine kinases.14 The HER receptor comprises extracellular, transmembrane, and intracellular domains. Eleven ligands are known to bind to the HER receptors (HER1, 3, and 4), which expose the dimerization domain and facilitate homo- and heterodimerization. In contrast, HER2 does not have a known ligand and adopts a constantly exposed dimerization domain with potent formation of homodimers.15 Dimerization results in the activation of the phosphoinositide 3-kinase (PI3K) and of the mitogen-activated protein kinase downstream signaling pathways with subsequent promotion of cell survival and proliferation.16

Targeting HER2 may encounter de novo or acquired resistances that are not yet fully elucidated. The available knowledge of de novo resistance describes phosphatase and tensin homolog (PTEN) deficiencies, PI3K mutation, loss of p27, and HER2 cleavage or allosteric hindrance.17–21 Acquired resistance occurs secondary to the increased activation of insulin-like growth factor 1 (IGFR1) and c-Met with enhanced release of the HER ligands and activation of downstream signaling.21–23 The presence of HER2 mutations may be another possible mechanism of resistance to anti-HER2 treatments.24,25 The potential development of resistance to anti-HER2 targeted agents represents an important rationale for implementing the dual targeting of the HER2 pathway.

Researchers discovered that the likelihood of a poor prognosis was increased for cases of cancer diagnosed after screening mammography with negative results versus those diagnosed after mammography with positive results.